Our vision is to represent the human musculoskeletal system, through the creation of data and models, with the realism needed to understand pathology and improve treatment. The human body is inherently multiscale. Diseases and injuries often affect tissues at the microstructural scale; small-scale pathology impacts biomechanics at larger scales, leading to whole-body movement compensations that oftentimes promote further injury or accelerate degeneration. Ultimately, a multiscale approach, describing the behavior of individual tissues, and the biomechanics of the whole body, is needed to elucidate the etiology of diseases, mechanisms of adaptation and best treatments. The overall goal of this proposal is to create a comprehensive multiscale neuromusculoskeletal model of the human lower extremity, which includes seamless connection between tissue and whole-body function during dynamic human activities and enables realistic investigations of musculoskeletal disease and treatment. While we will create and share models with broad applicability in biomechanics, our target is understanding the effects of knee osteoarthritis (OA) on patient function and optimizing treatment through total knee arthroplasty (TKA). OA is a serious degenerative joint disease and the leading cause of disability in the elderly. Moreover, OA is interrelated with many pressing health concerns, including obesity, cardiovascular disease (CVD), Alzheimer?s disease, dementia, and depression. Joint replacement remains the only effective treatment for advanced OA. Unfortunately, as many as 20-30% of total joint replacement patients report pain, require additional surgeries, and endure a poor movement-related quality of life. A tenet of our research is the use of human modeling and simulation to investigate the multiscale effects of OA on patients, and to improve the design and practice of joint replacement surgery.